A major problem in society concerns impairments in memory. These occur naturally with aging, as a result of stress and, in the extreme, in Alzheimer's disease. One brain structure, the hippocampus, is critical for key aspects of memory formation, and the most widely accepted possible mechanisms of memory storage in this structure are long-term potentiation (LTP) and long-term depression (LTD). There are age-related alterations in hippocampal LTP and LTD that correlate with age-impairments in hippocampal- dependent memory tasks. Recent evidence in humans suggests that estrogenic hormones appear to ameliorate early effects of Alzheimer's disease (and aging) on memory in women. Studies with rat brain slices in vitro indicate that estrogen (and testosterone) an modulate synaptic transmission in the hippocampus and our pilot data show that estrogen can markedly enhance LTP (CA1, clice). There appear to be sex differences in the inducibility of hippocampal LTP in animal models. Stress impairs hippocampal- dependent memory and we have shown that prior behavioral stress markedly impairs subsequent hippocampal LTP and enhances LTD in vitro, and that these effects are dependent upon the N-methyl-D- aspartate (NMDA) receptors. Our specific aims are thus to determine the effects of sex differences and estrogenic hormones on hippocampal plasticity (LTP and LTD), the roles of aging and stress on these effects, and possible mechanisms of action of these variables on hippocampal plasticity.